The milbemycins and avermectins are a series of macrolide antibiotics known to have closely related chemical structures and to exhibit highly potent anthelmintic, insecticidal, ectoparasiticidal and acaricidal activity. See M. H. Fisher and H. Mrozik, The Avermectin Family of Macrolide-Like Antibiotics, pp. 553-606, Macrolide Antibiotics: Chemistry, Biology, and Practice., ed. S. Omura, Academic Press (1984).
The known preparative procedures for these macrolides have employed fermentation techniques or lengthy syntheses unsuitable for preparation of various analogs.
The fermentation and isolation procedures, and the chemical structures and properties of the milbemycins and avermectins, are more fully described in U.S. Pat. Nos. 3,950,360; 3,984,564; 3,992,551; 4,093,629; and 4,144,352; Tetrahedron Letters, No. 10, pages 711-714, 1975; Journal of Antibiotics, Vol 29, No. 6, June, 1976, pages 76-35 to 76-42 and pages 76-14 to 76-16; Antimicrobial Agents and Chemotherapy, Volume 15, No. 3, March 1979, pages 361-367; and Journal of Antibiotics, Volume 33, No. 10, October, 1980, pages 1120-1127.
The total synthesis of milbemycin .beta..sub.3 is described in D. R. Williams et al., J. Am. Chem. Soc., 104, 4708-4710 (1982) and A. B. Smith et al., J. Am. Chem. Soc., 104, 4015-4018 (1982).
A lengthy synthesis of milbemycin .beta..sub.3 is also described in International Patent Application No.: PCT/US/82/01658, filed Nov. 22, 1982 and U.S. Pat. No. 4,408,059. At column 7, lines 42-51 of U.S. Pat. No. 4,408,059 the applicants speculate that a number of compounds, particularly the spiroketal compounds of Formua XXIV, include the chemical structure responsible for the biological activity of the various milbemycin and avermectin macrolides, and hence may themselves have utility as anthelmintic, insecticidal, ectoparasiticidal or acaricidal agents significantly simplified in chemical structure in comparison with the prior art compounds exhibiting similar biological activity.
The literature contains a number of syntheses of the 1,7-dioxaspiro[5.5]undecane system, many of which depend on the construction of a 1,9-dihydroxy-5-oxononane followed by intramolecular ketalization to generate the spiroketal. See, for example, K. Mori and K. Tanida, Synthesis of Three Stereoisomeric Forms of 2,8-Dimethyl-1,7-dioxaspiro[5,5]undecane, The Main Component of the Cephalic Secretion of Andrena Wilkella, Tetrahedron, 1981, 37, 3221; K. Mori and K. Tanida, Synthesis of Three Stereoisomeric Forms of 2,8-Dimethyl-1,7-dioxaspiro[5.5]undecane, The Main Component of the Cephalic Secretion of Andrena Wilkella, Heterocycles, 1981, 15, 1171; Y. Nakahara et al, Synthetic Studies of Antibiotic A23187 I. Chiral Synthons for C9-C13 and C14-C20, Tetrahedron Lett., 1981, 3197; D. A. Evans et al, Studies Directed Towards the Total Synthesis of the Ionophore Antibiotic A-23187, Tetrahedron Lett., 1978, 727; T. M. Cresp et al, An Approach to The Synthesis of Ionphores Related to A23187, Tetrahedron Lett., 1978, 3955. Other less general methods for preparing 5.5-spiroketals have been reported. See, for example, R. Baker et al, The Chemistry of Spiroketals.Enantispecific Synthesis of the Spiroketal Units of Avermectins B.sub.1b and B.sub.2b, J. Chem Soc., Chem Commun., 309-11, 1985; Hanessian, et al., Stereocontrolled Synthesis of the Spiroketal Unit of Avermectin B.sub.1a Agylone, J. Org. Chem., 1983, 48, pp 4427-30; J. Godoy et al., Synthesis of the Spiroacetal Unit Related to the Avermectins and Milbemycins, J. Chem. Soc., Chem,. Commun., 1381-82, (1984); P. Kocienski et al., A Synthesis of the Spiroacetal Moiety of Milbemycin .beta..sub.3, J. Chem. Soc., Chem. Commun., 571-73, (1984); D. R. Williams et al., Synthetic Studies of 1,7-dioxaspiro[5.5]undecan-4-ones, Tetrahedron Letters, Vol. 24, No. 5, p 427-30, 1983; P. Kocienski et al., A New Synthesis of 1,7-dioxaspiro[5.5]undecanes. Application to a Rectal Gland Secretion of the Olive Fruit Fly (Dacus oleae), Tetrahedron Letters, Vol. 24, No. 36, p 3905-06, 1983; I. T. Kay et al., Spiroketals: The Synthesis of an Olive Fly Pheromone Component, 4-hydroxy-1,7-Dioxaspiro[5.5]undecane, via a Novel Cation-Olefin Cyclisation Step, Tetrahedron Letters, Vol. 24, No. 52, p 5915-18, 1983; P. Kocienski et al., A Synthesis of Talaromycin B, J. Chem. Soc., Chem. Commun., 151-52, 1984.
K. J. Bruza, Studies of Synthetic Methodology Utilizing Cyclic Vinyl Ethers, Ph.D. Thesis, U of Michigan, 1979, describes the preparation of 6-oxo-2-methyldecane-1,2,10-triol which cyclizes to a 2,7-dioxabicyclo[3.2.1]octane in contrast to the dioxa[5.5]spiroketal system of the subject invention.
The diseases or groups of diseases described generally as helminthiasis are due to infection of the animal with parasitic worms known as helminths. Helminthiasis and helminthosis are prevalent and may lead to serious economic problems in sheep, swine, cattle, goats, dogs, cats, horses, poultry and man. Among the helminths, the groups of worms known as nematodes, trematodes and cestodes cause widespread and often-times serious infections in various species of animals including man. The most common genera of nematodes and cestodes infecting the animals referred to above are Dictyocaulus, Haemonchus, Trichostrongylus, Ostertagia, Nematodirus, Cooperia, Bunostomum, Oesophagostomum, Chabertia, Strongyloides, Trichuris, Fasciola, Dicrocoelium, Enterobius, Ascaris, Toxascaris, Toxocara, Ascaridia, Capillaria, Heterakis, Ancylostoma, Uncinaria, Onchocerca, Taenia, Moniezia, Dipylidium, Metastrongylus, Macracanthorhynchus, Hyostrongylus, and Stongylus. Some of these genera attack primarily the intestinal tract while others, inhabit the stomach, lungs, liver and subcutaneous tissues. The parasitic infections causing helminthiasis and helminthosis lead to anemia, malnutrition, weakness, weight loss, unthriftiness, severe damage to the gastrointestinal tract wall and, if left to run their course, may result in death of the infected animals.